Method for treating allergic reactions with Forskolin

ABSTRACT

Forskolin and its disclosed derivatives are useful as antiallergic agents. Certain of the derivatives are novel.

CROSS REFERENCE TO RELATED APPLICATION

This application is a file-wrapper-continuation of U.S. application Ser. No. 698,955, filed Feb. 6, 1985, now abandoned, which is a division of U.S. application Ser. No. 542,825, filed Oct. 17, 1983, now U.S. Pat. No. 4,517,200, which in turn is a continuation-in-part of U.S. application Ser. No. 453,436, filed Dec. 27, 1982, now abandoned.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,118,508 describes a chemical compound, Coleforsin, which is said to possess hypotensive and positive inotropic effects.

U.S. Pat. No. 4,134,986 describes polyoxygenated labdane derivatives which are also said to possess hypotensive and positive inotropic activities.

The compound, Forskolin (7β-acetoxy-8,13-epoxy-1α, 6β,9α-trihydroxylabd-14-en-11-one), is described in Arzneimittel-Forsch./Drug Res., 31, (II), 1248 (1981) as an adenylatecyclase activator.

J.C.S. Perkin I, 767 (1982) describes certain synthetic modifications of Forskolin.

The present invention provides a method for treating allergic reactions in a mammal which utilizes Forskolin and certain of its derivatives.

SUMMARY OF THE INVENTION

The invention sought to be patented in its pharmaceutical method aspect is a method for treating allergic reactions in a mammal which comprises administering an antiallergic effective amount of a compound having structural formula I in combination with a pharmaceutically acceptable carrier to said mammal, ##STR1## wherein R₁ and R₂ may be the same or different and are ═O, H, or OR₁₁ wherein R₁₁ is H, carboxylic acyl having from 1 to 6 carbon atoms or ##STR2## wherein m is 0, 1, 2 or 3 and Y is hydrogen, halogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, OH, CF₃, NO₂, CN, phenyl, benzyl, phenoxy or NR_(a) R_(b) wherein R_(a) and R_(b) are the same or different and are H or alkyl having from 1 to 6 carbon atoms;

R₁ and R₂ when taken together may form ##STR3## wherein R₁₃ and R₁₄ may be the same or different and are H, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon atoms, alkynyl having from 2 to 6 carbon atoms or ##STR4## wherein m and Y are defined above, or R₂ may be SO₃ OR' or OR' wherein

R' is alkyl having from 1 to 6 carbon atoms; R₃ is hydrogen; alkyl having from 1 to 10 carbon atoms; CH₂ OH; CHO; CO₂ R₁₅ wherein R₁₅ is H or alkyl having from 1 to 6 carbon atoms;

--CH═CR₁₆ R₁₇ wherein R₁₆ is H, halogen, alkyl having from 1 to 6 carbon atoms, ##STR5## wherein n is 0 or 1 and R_(c) is H, alkyl having from 1 to 6 carbon atoms, phenyl or benzyl, CHOHR_(c) or C(OR_(d))₂ R_(c) wherein R_(c) is defined above and R_(d) is alkyl having from 1 to 6 carbon atoms, R₁₇ is H, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, benzyl, phenyl or halogen;

--C.tbd.C--R₁₈ wherein R₁₈ is H, alkyl having from 1 to 12 carbon atoms, alkoxy having from 1 to 6 carbon atoms, ##STR6## CO₂ Rc or ##STR7## wherein Y and Rc are defined above; --CHOH--C.tbd.C--R₁₉ wherein R₁₉ is H, alkyl of from 1 to 6 carbon atoms, phenyl or benzyl;

--CH═C═CHR₁₉ wherein R₁₉ is defined above;

--CH═N--OR₁₉ wherein R₁₉ is defined above; ##STR8## wherein Z is O or S, and R₁₆ and R₁₉ are defined above; --CH(ZR₂₀)₂ wherein Z is defined above and R₂₀ is alkyl having from 1 to 6 carbon atoms, phenyl, benzyl or the two groups R₂₀ may together form --(CH₂)_(p) -- wherein p is 2 or 3; ##STR9## wherein A and B are H, halogen, alkyl having from 1 to 6 carbon atoms, phenyl, benzyl or ##STR10## wherein n and R_(c) are defined above; --CH═N--NDE wherein D and E are H, alkyl having from 1 to 6 carbon atoms, benzyl, phenyl, COG, SO₂ G, or CO₂ G wherein G is alkyl having from 1 to 6 carbon atoms, benzyl or phenyl;

R₄ is H or OH;

R₅ is OH; or when

R₄ and R₅ are taken together they may form ##STR11## wherein z is defined above; a is an optional bond which may be located in either the 5,6 or 6,7 position;

b is an optional bond, when present Q and R₃ are missing;

X is O or K/OR" wherein R" is hydrogen, carboxylic acyl having from 1 to 6 carbon atoms or trifluoroacetyl; and

Q is hydrogen, chlorine or bromine.

The preferred values for the above-defined substituents are as follows:

R₁ and R₂ may be the same or different and are hydrogen or OR₁₁ wherein R₁₁ is defined hereinabove and Y is hydrogen;

R₃ is hydrogen, alkyl having from 1 to 6 carbon atoms, --CH═CHR₃₀₁ or --C.tbd.CR₃₀₁ [wherein R₃₀₁ is hydrogen, alkyl having from 1 to 6 carbon atoms, phenyl, benzyl or CO₂ R_(c) ];

R₄ is H or OH;

R₅ is OH;

a is either not present or is located in the 5,6 position in which instance R₁ is preferably H and R₂ is preferably OR₁₁ wherein R₁₁ is defined hereinabove;

Y is hydrogen;

X is O or H/OH; and

Q is hydrogen or chlorine.

The invention sought to be patented in its first chemical compound aspect is a chemical compound having structural formula I as defined above wherein

R₄ is H; provided that 8,13-epoxy-1α6β,7β,11α-tetrahydroxylabd-14-ene is excluded.

The invention sought to be patented in its second chemical compound aspect is a chemical compound having structural formula I as defined above provided that when R₄ is OH then R₃ is not CH═CH₂, C₂ H₅, CHO or ##STR12##

The invention sought to be patented in its third chemical compound aspect is a chemical compound having structural formula I as defined above wherein

a is a 5,6 double bond;

R₁ is hydrogen; and

R₅ is hydroxy.

The invention sought to be patented in its fourth chemical compound aspect is a chemical compound having structural formula I as defined above wherein

a is a 5,6 double bond;

X is O or α-H/β-OH;

Q is H or Cl;

R₁ is H;

R₂ is OR₁₁ ;

R₃ is H, CH₃, CH₂ H₅ or CH═CH₂ ;

R₄ is H or OH; and

R₅ is OH.

Preferred chemical species of the invention are as follows:

8,13-epoxy-1α,6β,7β-trihydroxy-labd-14-en-11-one 7-acetate;

8,13-epoxy-1α,7β,9β-trihydroxy-labd-5(6)-ene-11-one 7-acetate;

8,13-epoxy-1α,6β,7β-trihydroxy-labd-14-en-11-one 6-acetate;

8,13-epoxy-1α,7β,9β-trihydroxy-labd-5(6),14-diene-11-one 7-acetate;

8,13-epoxy-1α,6β,7β-trihydroxy-labd-14-en-11-one;

8,13-epoxy-1α,6β,7β,11β-tetrahydroxy-labd-14-ene;

8,13-epoxy-1α,6β,7β,11β-tetrahydroxy-labd-14-ene-7-acetate;

12-chloro-8,13-epoxy-1α,7β-dihydroxy-labda-5(6), 14-dien-11-one 7-acetate;

15-nor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labdan-11-one;

15-nor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labdan-11-one 7-acetate;

8,13-epoxy-1α,7β,9α-trihydroxy-labd-5(6),14-diene 7-propionate.

The invention sought to be patented in a pharmaceutical composition aspect is a composition useful for treating allergic reactions in a mammal which comprises a compound having structural formula I in combination with a pharmaceutically acceptable carrier.

DESCRIPTION OF THE INVENTION

The compounds utilized in the method of the invention may be prepared by standard procedures. A convenient starting material for preparing these compounds is 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one, Forskolin, [J.C.S. Perkin I, 767 (1982)].

Those skilled in the art will recognize that in order to carry out a particular desired synthetic conversion it may be necessary to first protect other reactive sites which may be present in a molecule. Such protection is preferably accomplished by first forming a derivative at the site to be protected which derivative may be readily re-converted to the original functionality, if desired, after the particular synthetic conversion has been carried out. Examples of such protective conversions are esterification of alcohols and ketalization of ketones. Other such conversions will suggest themselves to those skilled in the art. Because such techniques are recognized as within the skill of the art, they are not included in the following description of the preparation of the compounds utilized in the method of the invention.

Compounds wherein R₁ is ═O may be prepared by oxidizing a corresponding compound wherein R₁ is OH. Compounds wherein R₁ is OR₁₁ may be prepared by acylation of a compound wherein R₁ is OH. Compounds wherein R₁ is H may be prepared by reduction of a compound wherein R₁ is ═O.

Compounds having R₂ substituents as described herein may be prepared substantially as described herein-above for a corresponding R₁ substituent.

Compounds wherein R₁ and R₂ together form ##STR13## may be prepared by reacting a corresponding compound wherein R₁ ═R₂ ═ OH with an aldehyde or ketone. Such reactions are generally carried out using conditions whereby the reaction-produced water may be continuously removed.

Compounds having the additional bond, a, may be produced for example by dehydration of a suitable compound wherein R₁ and/or R₂ are hydroxy.

Compounds wherein R₃ is CHO may be prepared from the starting compound (which has a vinyl group at this position) by ozonolysis. Compounds wherein R₃ is CH₂ OH or CO₂ R₁₅ may be prepared respectively by reducing or oxidizing the corresponding aldehyde. The carboxylic acid so produced (R₁₅ =H), thereafter may be esterified if desired. Compounds wherein R₃ is --CH═CR₁₆ R₁₇ may be prepared by treating a compound wherein R₃ is CHO with a Wittig reagent, φ₃ P═CR₁₆ R₁₇. Certain of the substituents, R₁₆ and R₁₇ may be modified or interconverted subsequent to the Wittig reaction, when desired. Compounds wherein R₃ is --C.tbd.C--R₁₈ may be prepared by treating a compound wherein R₃ is CHO with a reagent φ₃ P⁺ CHBrR₁₈ to produce a bromine containing intermediate which may be dehydrobrominated to produce the desired product. Compounds wherein R₃ is C.tbd.CH may be prepared by the addition of bromine to a corresponding compound wherein R₃ is --CH═CH₂ followed by didehydrobromination. Compounds wherein R₃ is --CHOH--C.tbd.C--R₁₉ may be prepared from a compound wherein R₃ is CHO by treatment with a reagent, MC.tbd.C--R₁₉, wherein M is a suitable metal such as lithium. Compounds wherein R₃ is --CH═C═CHR₁₉ may be prepared from a corresponding compound wherein R₃ is --CHOH--C.tbd.C--R₁₉ by first esterifying the hydroxyl group and treating the so obtained ester with aluminum chloride. Compounds wherein R₃ is --CH═N--OR₁₉ may be prepared from a compound wherein R₃ is CHO by treatment with a reagent of the formula H₂ N--OR₁₉. Compounds wherein R₃ is ##STR14## may be prepared from a compound wherein R₃ is --CH═CR₁₆ R₁₉ by treatment with a peracid such as m-chloroperbenzoic acid to produce compounds wherein Z is oxygen, these compounds may be converted to corresponding compounds wherein Z is sulfur by treatment with potassium isothiocyanate. Compounds wherein R₃ is --CH(ZR₂₀)₂ may be prepared from a compound wherein R₃ is CHO by treatment with an alcohol or thiol using standard procedures. Compounds wherein R₃ is ##STR15## may be prepared by the addition of a dihalocarbene to a compound wherein R₃ is --CH═CH₂ or by the addition of a methylene carbene to a compound wherein R₃ is --CH═CAB. Compounds wherein R₃ is --CH═N--NDE may be prepared by treating a compound wherein R₃ is CHO with a compound having the formula H₂ N--NDE using standard procedures.

Compounds wherein R₄ is hydrogen may be prepared, for example, by first forming an internal 1,9-carbonate or thiocarbonate ester utilizing a starting material wherein R₄ ═R₅ ═OH. Convenient reagents for performing these conversions are carbonyl diimidazole or thiocarbonyl diimidazole, respectively. The so produced esters upon treatment with zinc in acetic acid produce the compound wherein R₄ is hydrogen and R₅ is hydroxy.

The compounds of this invention wherein X is H/OH may be prepared by a suitable reduction of a compound wherein X is ═O.

When utilized herein the following terms will have the indicated meanings unless otherwise specified:

alkyl--straight and branched carbon chains having from 1 to 6 carbon atoms;

alkoxy and alkylthio--comprised of straight and branched carbon chains having from 1 to 6 carbon atoms which are singly bonded respectively to an oxygen or a sulfur atom;

halogen--fluorine, chlorine, bromine and iodine;

carboxylic acyl--the acyl portion derived from a straight or branched chain alkanoic acid having from 1 to 6 carbon atoms;

alkenyl--straight or branched carbon chains comprising one double bond and having from 2 to 6 carbon atoms;

alkynyl--straight and branched carbon chains comprising one triple bond and having from 2 to 6 carbon atoms.

The following numbering system is utilized herein for the Forskolin skeleton unless specified otherwise: ##STR16## a dashed line (----)indicates that the substituent is projected below the plane of the paper and is denoted as α; a heavy line ( ) indicates that the substituent is projected above the plane of the paper and is denoted as β.

The active compounds utilized in the method of this invention may exist as solvates, for example as hydrates.

Certain compounds of the invention may exist as optical and/or geometric isomers. For example, substituents at positions 6, 7 and 11 of the forskolin skeleton as well as certain R₃ substituents may exist in isomeric forms. In addition, when R₃ is hydrogen, both epimers at the C-13 carbon atom are included. The invention contemplates all isomers both in pure form and in admixture.

The compounds used in the methods of this invention can be used to treat allergy caused diseases and their preferred use is for treating allergic chronic obstructive lung diseases. Chronic obstructive lung disease as used herein means disease conditions in which the passage of air through the lungs is obstructed or diminished such as is the case in asthma, bronchitis and the like.

The anti-allergy method of this invention is identified by tests which measure a compound's inhibition of anaphylatic bronchospasm in sensitized guinea pigs having antigen induced bronchoconstriction. For example, the compound 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxy-labd-14-en-11-one was found to inhibit anaphylactic bronchospams in such test procedure when given at a dose of 1-3 mg/kg intravenously. Said compound was also found to inhibit allergen-induced histamine release from guinea pig and human sensitized tissue. The compounds are effective non-adrenergic, non-anticholinergic, antianaphylactic and bronchodilator agents. When administered orally they are active at doses of from about 0.2 to 20 mg/kg of body weight; when administered parenterally, e.g., intravenously, the compounds are active at dosages of from about 0.1 to 3 mg/kg body weight; when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.1 to 10 mg per puff, one to four puffs may be taken every 4 hours.

The amount, route and frequency of administration of the compounds will be regulated accordingly to the judgement of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the disease being treated. A typical recommended dosage regimen is oral administration of from 10 to 3000 mg/day, preferably 100 to 1000 mg/day, in two to four divided doses to achieve relief of the symptoms.

The compounds can be administered in conventional oral dosage forms such as capsules, tablets, pills, powders, suspensions or solutions prepared with conventional pharmaceutically acceptable excipients and additives, using conventional techniques. Parenteral preparations, i.e. sterile solutions or suspensions are also made by conventional means. Inhalation administration can be in the form of a nasal or oral spray. Insufflation is also contemplated. Topical dosage forms can be creams, ointments, lotions and the like. Other dosage forms which can be utilized are transdermal devices and suppositories.

The following test procedure was utilized to assess the usefulness of the compounds of the invention for inhibiting antigen induced anaphylactic bronchospasm.

Male Hartley guinea pigs were sensitized with 5 mg ovalbumin injected intraperitoneally (i.p.) and 5 mg injected subcutaneously (s.c.) in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4. The sensitized animals were used 3-4 weeks later.

To measure anaphylactic bronchospasm, sensitized guinea pigs were fasted overnight and the following morning anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 gm/ml diallylbarbituric acid, 0.4 gm/ml ethylurea and 0.4 gm/ml urethane). The trachea and jugular vein were cannulated and the animals were ventilated by a Harvard rodent respirator at 50 strokes/min with a stroke volume of 5 ml. A side arm to the tracheal cannula was connected to a Harvard pressure transducer to obtain an continuous measure of intratracheal pressure which was recorded on a Harvard polygraph. The recorder was calibrated so that a pressure of 50 mm Hg produced a 25 mm pen deflection. An increase in intratracheal pressure was taken as a measure of bronchoconstriction.

Each guinea pig was injected intravenously (i.v.) with 1 mg/kg dl-propranolol (HCl salt), 5 mg/kg indomethacin and 2 mg/ kg mepyramine (maleate salt) given together in a volume of 1 ml/kg. Fifteen minutes later, the animals were challenged with antigen (0.5 per cent ovalbumin) delivered as an aerosol generated from a DeVilbiss Model 65 ultrasonic nebulizer and delivered through the tracheal cannula for 30 seconds. Bronchoconstriction was measured as the peak increase in intratracheal pressure occurring within 15 minutes after antigen challenge.

Bronchoconstriction was studied in four guinea pigs at a time. The effect of test compound given i.v. on anaphylactic bronchospasm is expressed as per cent reversal of the peak increase in intratracheal pressure.

Results from the above procedure for representative compounds of the invention are given below.

    ______________________________________                                                                Percentage reversal                                     Forskolin derivative   at dose (mg/kg)                                         ______________________________________                                         8,13-Epoxy-1α,6β,7β,9α-tetrahydroxy-                                            70 (1)                                                  labd-14-en-11-one 7-acetate                                                                             65 (0.3)                                              (Forskolin)              43 (0.1)                                              8,13-Epoxy-1α,6β,7β,9α-tetrahydroxy-                                            69 (1)                                                  labd-14-en-11-one                                                              8,13-Epoxy-1α,6β,7β,9α-tetrahydroxy-                                            70 (1)                                                  labd-14-en-11-one 6-acetate                                                    8,13-Epoxy-1α,6β,7β,9α-tetrahydroxy-                                            30 (1)                                                  labdan-11-one 7-acetate                                                        8,13-Epoxy-1α,6β,7β,9α,11β-pentahydroxy-                                   33 (1)                                                  labd-14-ene 7-acetate                                                          8,13-Epoxy-1α,6β,7β,9α,11β-pentahydroxy-                                   25 (1)                                                  labd-14-ene                                                                    ______________________________________                                    

The following examples illustrate the preparation of representative compounds of the invention.

EXAMPLE I 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabdan- 11-one 7-acetate

Forskolin (30 mg) in MeOH (9 ml) with 10% Pd/C was hydrogenated at room temperature and atmospheric pressure for 2 hours. The catalyst was filtered off, and the solvent evaporated. Recrystallization from ether/hexane gave product, (16 mg) m.p. 242°-244° C.

EXAMPLE II 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one 7-acetate 1,9-thiocarbonate

Forskolin (100 mg) was stirred with carbonyl diimidazole (130 mg) in CH₂ Cl₂ (6 ml) at room temperature for 6 days. The solvent was evaporated and the residue chromotographed on a column of silica gel (10 g). Elution with 10% EtOAc/CHCl₃ gave product which was crystallized from ether/hexane (68 mg) m.p. 241°-243° C.

EXAMPLE III 8,13-Epoxy-1α,6β,7β-trihydroxylabd-14-en-11-one 7-acetate

The thiocarbonate of forskolin (0.23 g) from Example II in AcOH (11.5 ml) was treated with Zn powder (0.66 g) and was heated to 120° C. for 20 minutes. The zinc was filtered off hot, the filtrate poured into H₂ O (100 ml) and neutralized with NaOH. The product was extracted into ethyl acetate and chromotographed on a column of silica gel eluting with 10% EtOAc/CHCl₃ to give product which crystallized from acetone-hexane; (93 mg) m.p. 157.5°-160° C.

EXAMPLE IV

8,13-Epoxy-1α,7β,9α-trihydroxylabd-5(6)-en-11-one 7-acetate

Forskolin (1 g), benzyl bromide (0.82 ml), potassium iodide (1 g) and potassium carbonate (5 g) in 30 ml dry acetone was heated to 60° C. for 18 hours. After cooling the precipitate was filtered off, the filtrate was evaporated and the residue was separated on a column of silica gel (100 g) eluting with 5% EtOAc/CHCl₃ to give 1α-benzylforskolin (0.15 g). 80 mg of this material was treated with thionyl chloride (0.08 ml) in pyridine (0.8 ml) for 4 hours at 0° C. The reaction was poured into water and the product was isolated by extraction with ethyl acetate. This product was hydrogenated (PtO₂ 0.5 g, EtOAc 15 ml) for 24 hours at room temperature after which it was purified on a column of silica gel eluting with 20% EtOAc/hexane to give product crystallized from acetane hexane (19 mg).

EXAMPLE V 8,13-Epoxy-1α,6β,7β-trihydroxylabd- 14-en-11-one

9-Deoxyforskolin (0.44 g) prepared in Example III in methyl alcohol (21 ml) was treated with 5.28 ml of a 1.66% NaOH aqueous solution for 17 hours at room temperature. The resulting solution was neutralized with 2N HCl, the methanol was removed under reduced pressure and the product was taken into ethyl acetate. The organic layer was washed with water, dried (MgSO₄) and the solvent was evaporated to a residue which was purified on a column of silica gel (eluting with 40% EtOAc/hexane) to give product 0.15 g.

EXAMPLE VI A. 8,13-Epoxy-1α,6β,7β-trihydroxylabd-14-en-11-one 7-benzoate

The product from Example V (50 mg) was treated in pyridine (0.5 ml) at 0° C. with benzoyl chloride (0.018 ml) for 50 minutes. 2NHCl was added and then water; the product was isolated and purified on a column of silica gel eluting with 25% EtOAc/hexane. Crystallization from acetone-hexane gave product 33 mg m.p. 164.5° C.

B. 8,13-Epoxy-1α,6β,7β-trihydroxylabd-14-en-11- one 7-pentanoate

In a similar manner to Example VI A but substituting valeroyl chloride for benzoyl chloride, the product was obtained, m.p. 98°-100 ° C.

C. 8,13-Epoxy-1α,6β,7β-trihydroxylabd-14-en-11-one 7-(2-methylpropanoate)

In a similar manner to Example VI A but substituting 2-methylpropanoyl chloride for benzoyl chloride, the product was obtained, m.p. 145.5°-147.5° C.

EXAMPLE VII Forskolin 1,9-carbonate

A stirred and cooled (ice bath) solution of Forskolin (1 g) in dry methylene chloride (10 ml) and pyridine (3 ml) was treated with a solution of phosgene in methylene chloride (3 ml; approx. 13% phosgene by weight). After 45 minutes the starting material was all consumed. Methylene chloride and pyridine were removed in vacuo and the residue was distributed between methylene chloride (25 ml) and water (10 ml). The organic phase was separated and the aqueous phase extracted twice with methylene chloride. The combined organic extracts were dried (Na₂ SO₄) and evaporated to dryness to provide a crystalline solid, 1.29 gms. A 100 mg. portion of this product was recrystallized from ethyl acetate/n-hexane, m.p. 121°-123° C.

EXAMPLE VIII 14,15-Dinor-8,13-epoxy-13-formyl-1α,6β,7β,9α-tetrahydroxylabdan-11-one 1,9-carbonate

A solution of Forskolin 1,9-carbonate (0.2 g) prepared as in Example VII in methylene chloride (4 ml) and methanol (3 ml) was cooled in acetone/dry ice bath. Ozone/oxygen was passed through this solution until excess ozone (indicated by blue coloration) was present (approx. 5-7 minutes). Excess ozone was driven off by passing argon through the solution and 0.5 ml dimethylsulfide was added. The reaction mixture was gradually allowed to warm to room temperature and after stirring 2 hours, evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (15 ml) and washed with water. The methylene chloride solution was dried (Na₂ SO₄) and evaporated to dryness to yield a crystalline product nearly homogenous by TLC. Yield: 0.190 g. A 20 mg. portion was recrystallized from ethyl acetate/n-hexane, m.p. 237°-238° C.

EXAMPLE IX 15-Nor-8,13-epoxy-1α,6β,7β,9β-tetrahydroxy-14-hydroxyiminolabdan-11-one 7-acetate 1,9-carbonate

A solution of the aldehyde (0.4 g) prepared as in Example VIII in dry pyridine (5 ml) was cooled (ice bath) and treated with solid NH₂ OH.HCl (0.07 g) with stirring. After approximately 2 hours the reaction mixture was diluted with methylene chloride (25 ml) and treated with dilute H₂ SO₄ (0.1N) until the aqueous phase was acidic. The methylene chloride layer was separated, and the aqueous phase was extracted once with methylene chloride. The combined methylene chloride extracts were washed once with water, dried (Na₂ SO₄) and evaporated to dryness to provide a crystalline TLC homogenous product. Yield: 0.38 g. A small portion of this product (30 mg.) was recrystallized from chloroform to provide colorless cubes, m.p. 277°-280° C.

EXAMPLE X 14,-E and Z-8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one 7-acetate 1,9-carbonate 15-methylcarboxylate

A solution of the aldehyde (0.1 g) as prepared in Example VIII in methylene chloride (5 ml) was treated with the phosphorane (Ph₃ P═CH.COOMe) (0.085 g; ca. 1.1 equiv.) and the reaction mixture refluxed for 2 hours. TLC showed a two-component mixture. Refluxing for an additional 2 hours did not change the product ratios by TLC. The methylene chloride was replaced by benzene (4 ml), additional phosphorane (0.04 g) was added and the reaction mixture again refluxed for 1 hour. The benzene was evaporated to dryness in vacuo and the residue subjected to chromatography on two 1 mm thick silica gel plates using 40% acetone/n-hexane as eluent:

    ______________________________________                                         LESS POLAR COMPONENT A                                                                              0.08 g. crystals                                          (Z-isomer)           m.p. 120-121° C.                                   MORE POLAR COMPONENT B                                                                              0.04 g. crystals                                          (E-isomer)           m.p. 214-216° C.                                   ______________________________________                                    

EXAMPLE XI 8,13-Epoxy-1α,7β,9α-trihydroxylabda-5(6), 14-diene-11-one 7-acetate 1,9-carbonate

To a stirred solution of forskolin 1,9-carbonate (0.87 g,) from Example VII in dry CH₂ Cl₂ (17.4 ml) was added diethylaminosulfurtrifluoride (0.5 ml) under a nitrogen atmosphere at 0° C. After stirring for 15 minutes, another portion of diethylaminosulfurtrifluoride (0.5 ml) was added and stirred for a further 30 minutes. EtOAc (200 ml) was added to the mixture and then washed immediately with saturated NaHCO₃ solution and water. The organic fraction was dried (MgSO₄) and evaporated in vacuo to dryness to yield a white solid, 0.79 g (95%). A portion of product was crystallized from EtOAc/hexane to give product m.p. 164°-166° C.

EXAMPLE XII (a) 8,13-Epoxy-1α,7β,9α-trihydroxy-labda-5(6), 14-diene-11-one and (b) 8,13-Epoxy-1α,7β,9β-trihydroxy-labd-5(6),14-diene-11-one 7 acetate

A mixture of 8,13-epoxy-1α,7β,9α-trihydroxy-labd-5(6),14-diene-11-one 7-acetate 1,9-carbonate (0.78 g), prepared as in Example XI, MeOH (40 ml) and NaOH solution (1.66% in H₂ O, 5 ml) was stirred at room temperature for 3.5 hours. An additional NaOH solution (1.66% NaOH in H₂ O, 5 ml) was added and stirred for a further 30 minutes. The mixture was neutralized with a few drops of HCl (2N) and the solution was evaporated in vacuo. The residue was redissolved in EtOAc and washed with brine, dried (MgSO₄) and concentrated under reduced pressure to give a white solid, 0.64 g. Column chromatography (100 g silica gel, 40% EtOAc/CHCl₃) afforded 8,13-epoxy-1α,7β,9α-trihydroxy-labda-5(6),14-diene-11-one 0.51 g (78%) which was crystallized from acetone/hexane, m.p. 179°-181° C. and 8,13-epoxy-1α,7β,9α-trihydroxy-labd-5(6),14-diene-11-one 7-acetate 0.13 g (18%) which was crystallized from ethylacetate/hexane, m.p. 119°-121° C.

EXAMPLE XIII 8,13-Epoxy-1α,7β,9α-trihydroxy labda-5(6), 14-diene-11-one 7-propionate

To a cooled solution of 8,13-epoxy-1α,7β,9α-trihydroxy-labd-5(6),14-diene-11-one (40 mg,) prepared as in Example XII in distilled pyridine (0.4 ml) was added propionic anhydride (0.2 ml) at 0° C. (ice-water bath). The mixture was stirred at 0° C. for 2.5 hours then at room temperature for 2 hours. The mixture was diluted with EtOAc (200 ml) and washed with 1N HCl, H₂ O and dried (MgSO₄). The solvent was evaporated in vacuo to a residue which was purified on thin layer chromatography plate (silica plates, 1 mm, 40% EtOAc/hexane) to give product 26 mg (0.64 mmol, 56%). Crystallization from petroleum ether gave product 20 mg. m.p. 109.5° C.-111° C.

EXAMPLE XIV 8,13-Epoxy-1α,7β,9α-trihydroxy-labda-5(6), 14-diene-11-one 7-methylether

To a mixture of sodium hydride (60%, 5.7 mg) in THF (freshly distilled, 0.3 ml) was added CH₃ I (0.009 ml, 0.14 mmol) and the product from Example XIIa (25 mg, 0.07 mmol) in 0.3 ml of THF under a nitrogen atmosphere. The mixture was heated at 60° C. for 30 minutes and quenched with a few drops of 1N HCl. Solvent was evaporated and the residue was separated on thin layer chromatography plates (silica gel, 40% EtOAc/Hexane) to give product 12 mg, (0.033 mmol, 46%) which crystallized from EtOAc/Hexane to give product 10 mg m.p. 133°-135° C.

EXAMPLE XV 8,13-Epoxy-1α,6β,7α-trihydroxy-labda-14-en-11-one 7-methanesulfonate

A mixture of the product from Example V (50 mg) in pyridine (0.5 ml) and CH₃ SO₂ Cl (25 μl) was stirred at room temperature for 1 hour. EtOAc (200 ml) was added to the mixture and washed immediately with 1N HCl and then with H₂ O. The organic phase was dried (MgSO₄) and evaporated in vacuo to give a residue 54 mg. Purification on silica gel thin layer chromatography plates, (10% EtOAc/CHCl₃) yielded product 33 mg (0.073 mmol, 54%) m.p. 90°-92° C.

EXAMPLE XVI 8,13-Epoxy-1α,7β,9α,11β-tetrahydroxy labda-5(6),14-diene

A mixture of the product from Example VII (forskolin 1,9-carbonate) (90 mg, 0.215 mmol) in THF (1 ml) ethylether (3.6 ml) and lithium aluminum hydride (45 mg, 1.18 mmol) was heated at 40° C. under a nitrogen atmosphere for 1 hour. To the cooled mixture (in ice-water bath) was added 50 ml Et₂ O and 0.2 ml of saturated Na₂ SO₄ solution and stirred for 0.5 hour. The white precipitate was filtered off and washed with Et₂ O (50 ml). The filtrate was evaporated under reduced pressure to give a white residue 80 mg. This residue was purified on silica gel thin layer chromatography plates, (40% EtOAc/Hexane) to yield product 28 mg (0.079 mmol, 37%). Crystallization from EtOAc/Hexane gave product 22 mg. m.p. 120°-126° C.

EXAMPLE XVII 8,13-Epoxy-1α,6β,7β,11β-tetrahydroxy labd-14-ene

A mixture of product from Example III (9-deoxyforskolin) (15 mg, 0.14 mmol) in Et₂ O (3.0 ml) and lithium aluminum hydride (25 mg, 0.66 mmol) was heated to 40° C. under a nitrogen atmosphere for 1.5 hours. The mixture was diluted with Et₂ O (50 ml) and cooled in ice-water bath. To the cooled mixture was dropwise added saturated Na₂ SO₄ /H₂ O solution (1 ml) and stirred for 30 minutes. The white precipitate was filtered off and washed with Et₂ O (50 ml). The organic solution was concentrated in vacuo to give a residue 44 mg. Purification of the residue on alumina TLC plate (250μ, 5% EtOAc-1% MeOH -94% CHCl₃) yielded product 23 mg (0.5 mmol, 46%) which crystallized from EtOAc/hexane, 21 mg m.p. 189°-190° C. cl EXAMPLE XVIII

8,13-Epoxy-1α,6β7β,11β-tetrahydroxy labd-14-ene 7-acetate

To a solution of crude product (94 mg, 0.265 mmol), prepared as in Example XVII, in pyridine (0.94 ml) and CH₂ Cl₂ (0.14 ml) was added acetic anhydride (0.135 ml, 1.32 mmol). The mixture was stirred at room temperature overnight, H₂ O (100 ml) was added to quench the reaction and product was extracted with EtOAc. The organic layer was washed with 1N HCl, H₂ O and dried (MgSO₄). The solvent was evaporated in vacuo to give a residue. Column chromatography on silica gel, (2% MeOH/CHCl₃) gave product 49 mg (47%) m.p. 132°-136° C.

EXAMPLE XIX 15-Nor-1,13-epoxy-1α,6β,7β,9α-tetrahydroxy -14-dithioethylene-labdan-11-one-7-acetate; 1,9-carbonate

A solution of the product from Example VIII (100 mg) in 5 ml dry CH₂ Cl₂ containing 40 μl ethanedithiol was cooled to -78° C. under N₂. To this was added 60 l of BF₃. Et₂ O and the reaction was allowed to stir at this temperature for 1 hour. The reaction mixture was quenched with water and extracted with CH₂ Cl₂. The organic extract was washed with dilute NH₄ OH solution dried (Na₂ SO₄) and the solvent removed, to give the product (purified by preparative TLC eluting with 50% EtOAc/hexane) 80 mg, m.p. 285°-287° C. (d).

EXAMPLE XX 15-Nor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-14-dithioethylene-labdan-11-one

A solution of the product from Example XIX (32.1 mg) in methanol (6.0 ml) was treated with 10% NaOH (1.5 ml). The reaction was allowed to stir for 16 hours. Oxalic acid (112.5 mg) was added and the product was extracted with CH₂ Cl₂, separated and dried. Solvent removed to give the product 30 mg.

EXAMPLE XXI 15-Nor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-14-dithioethylene-labdan-11-one-7-acetate

The product from the Example XX (69.5 mg) was acylated in dry pyridine (0.7 ml), with Ac₂ O (73.4 l) and dry CH₂ Cl₂ (0.7 ml) in a similar manner as in Example XXIII. Purification by preparative TLC, eluting with EtOAc/MeOH/CHCl₃ (5:1:94), afforded product 38.4 mg white solids m.p. 216°-218° C. (d).

EXAMPLE XXII 15-Nor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labdan-11-one

The product from Example XXI (165 mg) was desulfurized with 9 ml Ra/Ni suspension in 16 ml ethanol. The mixture was allowed to stir at room temperature for 16 hours. After filtration and washing with ethanol, the solvent was removed to give 112 mg. of the product. Recrystallization from methanol afforded white crystals of the product m.p. 191°-192° C.

EXAMPLE XXIII 15-Nor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy labdan-11-one-7-acetate

The product from Example XXII (91 mg) was dissolved in 0.8 ml dry pyridine and was treated with a solution of acetic anhydride (0.093 ml) in dry methylene chloride (0.8 ml). The reaction mixture was allowed to stir at room temperature under N₂ for 16 hours. The mixture was distributed between water and methylene chloride, the organic layer was washed with dilute HCl, dried and the solvent removed to give the product 87.4 mg. This crude product, purified by preparative TLC, eluting with 2% MeOH/CHCl₃, gave 40 mg crystalline product m.p. 274°14 276° C.

EXAMPLE XXIV 14,15-Dinor-13-cyclopropyl-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labadan-11-one-7-acetate

A solution of forskolin (100 mg) in dry THF (1.0 ml) was treated with diazomethane in ether solution (3 ml) at 0° C. A small amount of Pd(OAc)₂ was added and the reaction mixture was stirred at this temperature for 15 minutes. The product was isoluted and purified by preparative TLC, eluting with 5:1:94 ratio of EtOAc:MeOH:CHCl₃. Crystalliation from CHCl₃ gave the product 65 mg, white crystals m.p. 253°-256° C.

EXAMPLE XXV 14,15-Dinor-13-cyclopropyl-8,13-epoxy-1α,6β,7β-hydroxy-labadan-11-one-7-acetate

9-Deoxyforskolin (100 mg) prepared as in Example III was cyclopropanated in a similar manner as in Example XXIV. The product was purified on a column of silica gel, eluting with 20% EtOAc/CHCl₃, and was further purified by preparative TLC, eluting with 30% EtOAc/CHCl₃, to give the product 53.2 mg. Crystallization from diisopropylether gave m.p. 205°-205° C.

EXAMPLE XXVI 8,13-Epoxy-1α,6β,7β-trihydroxy-labd-14-en-11-one 6-acetate

A mixture of product from Example II (500 mg, 1.4 mmol), acetic acid (25 ml) and Zn powder (1.44 g) was heated at 120° C. under a nitrogen atmosphere. After 30 minutes, another portion of Zn powder (1.44 g) was added and the mixture heated for a further 30 minutes. After cooling, the zinc was filtered off and the filtrate was concentrated in vacuo to a residue which was redissolved in EtOAc (300 ml), washed with water and dried (MgSO₄). The organic solvent was evaporated in vacuo and the residue was chromatographed on a column of silica gel eluting with 10% EtoAc/CHCl₃ to give 9-desoxy forskolin 308 mg and product 40 mg. A 30 mg portion of the product was crystallized from acetone-hexane to give m.p. 190°-192° C.

EXAMPLE XXVII 8,13-Epoxy-1α,7β-dihydroxy-labda-5(6),14-diene-11-one 7-acetate

To a solution of the product from Example XI (70 mg 0.167 mmol) in acetic acid (3.5 ml) was added Zn powder (0.21 g). The mixture was heated to 120° C. under a nitrogen atmosphere for 1.5 hours. EtOAc (100 ml) was added and the Zn was filtered off. The filtrate was poured into H₂ O (50 ml), neutralized with NaOH and the product was extracted into ethyl acetate. Chromatograph on a column of silica gel eluting with 30% EtOAc/hexane gave the product which was crystallized from ethyl acetate-hexane (14 mg).

EXAMPLE XXVIII 12-Chloro-8,13-epoxy-1α,7β-dihydroxy-labda-5(6),14-diene-11-one 7-acetate

A mixture of the product from Example II (140 mg, 0.309 mmol) in pyridine (2.1 ml) and SOCl₂ (0.21 ml) was stirred at room temperature for 20 minutes. Water was added to the mixture and neutralized with 2N HCl. The product was extracted into ethyl acetate and, after work up, was chromatographed on silica TLC plates (1 mm, 10% EtOAc/CHCl₃) to give product 20 mg, m.p. 103°-105° C.

EXAMPLE XXIX 8,13-Epoxy-1α,7β,9α-trihydroxy-labda-5(6),14-diene-11-one 7-butyrate

A solution of product Example XIIa (44 mg, 0.114 mmol) in pyridine (0.4 ml) and butyric anhydride (0.2 ml) was stirred at 0° C. for 24 hours. H₂ O was added at 0° C to quench the reaction and the mixture was diluted with EtOAc (200 ml). The organic solution was washed with 0.1N HCl, saturated NaHO₃ solution, water and dried (MgSO₄). The solvent was evaporated in vacuo to give a residue (45 mg). Purification on silica TLC plates (1 mm, 40% EtOAc-hexane) yielded product 26 mg (0.061 mmol, 54%) which was crystallized from petroleum ether to give m.p. 75°-77° C.

EXAMPLE XXX 8,13-Epoxy-1α,6β,7β,9α-tetrahydroxy-labd-14-en-11-one 6,7-ethylorthoacetate

To a solution of 8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labd-14-en-11-one (800 mg, 0.217 mmol) in dry DMSO (7.05 ml) was added p-toluenesulfonic acid (63.5 mg) and triethylorthoacetate (1.53 ml). The mixture was stirred at room temperature for 2.3 hours, 5% aqueous Na₂ CO₃ (100 ml) was added and the product was extracted with ethyl acetate. The combined EtOAc extracts were washed with water, dried (MgSO₄ ) and evaporated in vacuo to give product (930 mg, 0.272 mmol, 98%). A 100 mg portion of product was crystallized from EtOAc/hexane to give product m.p. 190.5°-193° C.

EXAMPLE XXXI 8,13-Epoxy-1α,9α-dihydroxy-labda-6(7),14-dien-11-one

Forskolin (1 g), p-methoxybenzyl chloride (1.0 ml), potassium iodide (1 g) and potassium carbonate (5 g) in 30 ml dry acetone was heated at 60° C. for 18 hours. After cooling, the precipitate was filtered off, the filtrate evaporated and the residue was separated on a column of silica gel (100 g) eluting with 10% EtOAc/CHCl₃ to give 1α-p-methoxybenzyl forskolin (0.4 g) and 0.8 g of a mixture of 1α-p-methoxybenzyl forskolin and 1α-p-methoxybenzyl-6-acetate-7-deacetyl forskolin. This mixture (0.8 g) was treated with MeOH (43.2 ml) and 1.66% NaOH-H₂ O (10.8 ml) at room temperature overnight. The MeOH was evaporated in vacuo and the residue was dissolved in EtOAc (300 ml), washed with water and dried (MgSO₄ ). Purification on a silica gel column yielded 1α-p-methoxy benzyl-7-deacetyl forskolin (0.63 g). This product was treated with toluene (20 ml), thiocarbonyldiimidazole (765 mg) and N,N-dimethylaminopyridine (63 mg) at 100° C. under a nitrogen atomosphere for 24 hours. After evaporating off the solvent in vacuo, the residue was chromatographed on a column of silica gel (70 g, 20% EtOAc/hexane) to give 1α-p-methoxybenzyl-6β,7β-thiocarbonate 7-deacetyl forskolin (0.59 g). A portion of this product (250 mg) was heated in the presence of 1,3-dimethyl-2-phenyl-1,3-diazo-2-phosphacyclopentane (1.25 ml) at 50° C. under an argon atmosphere in a reacti-vial for 1 day. Chromatography on a silica gel column (300 g, 15% EtOAc/hexane) gave 8,13-epoxy-1α,9α-dihydroxy-labda- 6(7),14-diene-11-one 1α-p-methoxy benzyl ether (62 mg). This product was treated with CH₂ Cl₂ : H₂ O (18:1) (3.0 ml) and DDQ (68.1 mg) at room temperature for 1 day. A further portion of DDQ (25 mg) was added and stirred at room temperature for a further day. The mixture was then filtered through celite, washed with acetone and the product purified on a silica gel columm (50 g, 30% EtOAc/hexane) to give 8,13-epoxy-1α,9α-dihydroxy-labda-6(7),14-diene-11-one 1α-p-methoxybenzoate (60 mg). This product (60 mg) was hydrolyzed with 1.66% NaOH-H₂ O (0.72 ml) in the presence of MeOH (3.0 ml) for 28 hours at room temperature. The resulting solution was neutralized with 2N HCl and the methanol was removed under reduced pressure. The product was dissolved in EtOAc, washed with water, dried (MgSO₄), evaporated in vacuo to a residue and purified on a column of silica gel (100 g, 10% EtOAc/hexane) to give product 40 mg. A 20 mg portion was crystallized from n-hexane, to give product m.p. 92°-93° C.

EXAMPLE XXXII 8,13-Epoxy 1α,9α-dihydroxy-labda-5(6),14-diene-7,11-dione

To a solution of the product from Example XIIa (50 mg) in CHCl₃ (3.0 ml) was added activated MnO₂ (50 mg, 0.575 mmol). The mixture was stirred at room temperature and additional activated MnO₂ (50 mg) was added on each of the following 2 days. On the third day, the mixture was diluted with CHCl₃ (100 ml) and filtered through a celite pad which was washed with additional CHCl₃ (50 ml). The filtrate was concentrated in vacuo to give a residue 45 mg. Chromatography on a silica gel column (40% EtOAc-CHCl₃) yielded product 14 mg (0.04 mmol, 28%). Crystallization from EtOAc/hexane gave product 10 mg, m.p. 205°-208° C.

EXAMPLE XXXIII 14,-E and Z-8,13-epoxy-1α,6β,7β-trihydroxy-labd-14-en-11-one 7-acetate 15-methylcarboxylate

A solution of 14,15-dinor-8,13-epoxy-13-formyl-1α,6β,7β-trihydroxy-labdan-11-one 7-acetate (obtained from ozonolysis of 9-deoxyforskolin, 100 mg as in Example XXXIV) in CH₂ Cl₂ was treated with the phosphorane (Ph₃ P═CH.COOMe; 90 mg). The reaction mixture was stirred at room temperature for 48 hours. The methylene chloride was evaporated in vacuo to provide a gummy residue which was chromatographed on silica gel TLC plates using 40% ethyl acetate/n-hexane as eluent to give the less polar Z-isomer as a colorless amphorphous solid (17.6 mg) and the more polar E-isomer as a colorless amphorphous solid (47.0 mg).

EXAMPLE XXXIV

14,15-Dinor-8,13-epoxy-13-formyl-1α,6β,7β-trihydroxy-labdan-11-one 7-acetate

Ozone was passed through a cooled solution (bath temp. -70°) of 9-deoxy forskolin (50 gm) in methylene chloride (4 ml and methanol (3 ml) until the blue coloration persisted. Excess ozone was flushed out with nitrogen followed by addition of 0.1 ml of Me₂ S. The solution was gradually allowed to warm to room temperature (approx. 45 minutes) after which the solvents were evaporated in vacuo to provide a gummy residue. It was dissolved in CH₂ Cl₂, the solution dried over Na₂ SO₄ and evaporated to dryness. The so obtained aldehyde which was almost pure (TLC; solvent system 20% EtOAc/chloroform) was used as such in the following reactions.

EXAMPLE XXXV 15-Nor-8,13-epoxy-1α,6β,7β-trihydroxy-14-methoximino-labdan-11-one 7-acetate

A solution of 14,15-dinor-8,13-epoxy-13-formyl-1α,6β,7β-trihydroxy-labdan-11-one 7-acetate [as obtained from ozonolysis of 9-deoxy-forskolin, (50 mg) in Example XXXIV] in dry pyridine (2 ml) was treated with NH₂ OCH₃.HCl (12 mg). The mixture was stirred at room temperature for 2 hours after which, the pyridine was removed in vacuo. The resulting solid was distributed between CH₂ Cl₂ and water. After separation of the organic phase, the aqueous phase was extracted once more with CH₂ Cl₂. The combined methylene chloride extracts were dried over Na₂ SO₄ and evaporated to dryness to provide a gummy solid which was subjected to chromatography on silica gel TLC plates using 20% ethyl acetate in chloroform as eluent. Extraction of the major band with ethyl acetate provided the pure title compound as a colorless amorphous solid.

EXAMPLE XXXVI 14,15-Dinor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labd-12-en-11-one 7-acetate 1,9-carbonate

A solution of the product from Example IX (0.665 g) in CH₂ Cl₂ (60 ml) was treated with carbonyl diimidazole (0.266 g) for 2 hours at room temperature. The organic solution was washed with H₂ O, dried (Na₂ SO₄) and evaporated to a solid residue. Purification by preparitive TLC (eluent 20% EtOAc/CHCl₃) gave the product (0.45 g.) m.p. 264°-5° C. after crystallization from EtOAc/hexane.

EXAMPLE XXXVII 14,15-Dinor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labd-12-en-11-one

A solution of the product from Example XXXVI (0.1 g) in MeOH (8 ml) was treated with 10% NaOH (4 ml) for 15 hours at room temperature. Aqueous oxalic acid was added and the product was extracted into CH₂ Cl₂. The organic solution was washed with water, dried (Na₂ SO₄) and evaporated to give the product (0.094 g).

EXAMPLE XXXVIII 14,15-Dinor-8,13-epoxy-1α,6β,7β,9α-tetrahydroxy-labd-12-en-11-one 7-acetate

The product from Example XXXVII (0.06 g) in dry pyridine (0.6 ml) and CH₂ Cl₂ (0.8 ml) was treated with acetic anhydride (0.06 ml) for 20 hours at room temperature. Water was added and after 1 hour the reaction mixture was evaporated to a residue that was purified by preparitive TLC (eluent 20% EtOAc/hexane) to give the product (0.03 g), m.p. 224°-5° C. after crystallization from EtOAc/hexane.

EXAMPLE XXXIX 8,13-Epoxy-1α,6β,7β,trihydroxy-labd-14-en-11-one 6,7-acetonide

The product from Example V (0.1 g) in dry acetone (10 ml) was treated with trimethylsilyl chloride (0.1 ml) at room temperature. After 15 hours a further portion of trimethylsilyl chloride (0.1 ml) was added and after another 15 hours the reaction was diluted with saturated NaHCO₃ solution. The product was extracted into CH₂ Cl₂ and the organic extract was washed with H₂ O, dried (Na₂ SO₄) and evaporated to a residue that was purified by preparitive TLC (eluent 10% EtOAc/CHCl₃) to give the product (0.045 g), m.p. 146°-7° C. from EtOAc/hexane.

EXAMPLE XL 13-Epi-14,15-dinor-8,13-epoxy-1α,6β,7β,9α,11- pentahydroxy-labdane 1,9-carbonate 7-acetate

The product from Example XXXVI (0.1 g) in EtOH (10 ml) was hydrogenated at 50 psi at room temperature for 36 hours in the presence of PtO₂ (0.1 g). The catalyst was then filtered off, the filtrate evaporated to a residue which was purified by preparitive TLC to give the product (0.67 g).

EXAMPLE XLI 13-Epi-14,15-dinor-8,13-epoxy-1α,6β,7β,9α,11-pentahydroxy-labdane 7-acetate

A solution of the product from Example XL (0.067 g) in MeOH (5 ml) was stirred overnight at room temperature with 10% NaOH solution (2 ml). Aqueous oxalic acid was added and the product extracted into CH₂ Cl₂. The organic layer was washed with H₂ O, dried (Na₂ SO₄) and evaporated to a residue of 13-epi-14,15-dinor-8,13-epoxy-1α,6β,7β,9α,11-pentahydroxy-labdane. This material was dissolved in pyridine (0.7 ml) and CH₂ Cl₂ (0.7 ml) and treated with Ac₂ O for 20 hours at room temperature. Water was added and the product extracted into CH₂ Cl₂ ; the organic extract was washed with H₂ O, dried (Na₂ SO₄) and evaporated to a residue which was purified by preparitive TLC (eluent EtOAc/MeOH/CHCl₃ -5/1/94) to give the product (0.024 g), m.p. 234°-240° C. from EtOAc/hexane. 

We claim:
 1. A method for treating allergic reactions in a mammal which comprises administering a bronchodilating effective amount or an amount effective to inhibit histamine release of a compound having structural formula I ##STR17## in combination with a pharmaceutically acceptable carrier to said mammal, wherein one of R₁ and R₂ may be ═O and the other of R₁ and R₂ may be H, or OR₁₁ or both of R₁ and R₂ may be H or OR₁₁ wherein R₁₁ is H, alkanoyl having from 1 to 6 carbon atoms or ##STR18## {wherein m is 0, 1, 2 or 3 and Y is hydrogen, halogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, alkylthio having from 1 to 6 carbon atoms, OH, CF₃, NO₂, CN, phenyl, benzyl, phenoxy or NR_(a) R_(b) wherein R_(a) and R_(b) are the same or different and are H or alkyl having from 1 to 6 carbon atoms}; orR₁ and R₂ may be taken together to form ##STR19## wherein R₁₃ and R₁₄ may be the same or different and are H, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, alkenyl having from 2 to 6 carbon, alkynyl having from 2 to 6 carbon atoms, or ##STR20## wherein m and Y are as defined above, or R₂ may be SO₃ OR' or OR' wherein R' is alkyl having from 1 to 6 carbon atoms; R₃ is hydrogen, alkyl having from 1 to 10 carbon atoms, CH₂ OH, CHO, CO₂ R₁₅ {wherein R₁₅ is H or alkyl having from 1 to 6 carbon atoms}, --CH═CR₁₆ R₁₇ {wherein R₁₆ is H, halogen, alkyl having from 1 to 6 carbon atoms, ##STR21## (wherein n is 0 or 1 and R_(c) is H, alkyl having from 1 to 6 carbon atoms, phenyl or benzyl), CHOHR_(c) or C(OR_(d))₂ R_(c) (wherein R_(c) is defined above and R_(d) is alkyl having from 1 to 6 carbon atoms), and R₁₇ is H, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, benzyl, phenyl or halogen}, --C.tbd.C--R₁₈ {wherein R₁₈ is H, alkyl having from 1 to 12 carbon atoms, alkoxy having from 1 to 6 carbon atoms, ##STR22## CO₂ Rc or ##STR23## wherein Y and R_(c) are defined above}, --CHOH--C.tbd.C--R₁₉ {wherein R₁₉ is H, alkyl of from 1 to 6 carbon atoms, phenyl or benzyl}, --CH═C═CHR₁₉ {wherein R₁₉ is defined above}, --CH═N--OR₁₉ {wherein R₁₉ is defined above}, ##STR24## {wherein Z is O or S, and R₁₆ and R₁₉ are defined above }, --CH(ZR₂₀)₂ {wherein Z is defined above and R₂₀ is alkyl having from 1 to 6 carbon atoms, phenyl, benzyl or the two groups R₂₀ may together form --(CH₂)_(p) -- wherein p is 2 or 3}, ##STR25## {wherein A and B are H, halogen, alkyl having from 1 to 6 carbon atoms, phenyl, benzyl or ##STR26## wherein n and R_(c) are defined above}, --CH═N--NDE {wherein D and E are H, alkyl having from 1 to 6 carbon atoms, benzyl, phenyl, COG, SO₂ G, CO₂ G (wherein G is alkyl having from 1 to 6 carbon atoms, benzyl or phenyl)}; R₄ is H or OH; R₅ is OH; or when R₄ and R₅ are taken together they may form ##STR27## wherein Z is defined above; a is an optional bond which may be located in either the 5,6 or 6,7 position, such that when a is a 5,6 bond, R₂ is ═O, H or OR₁₁ with R₁₁ equal to H, alkanoyl or ##STR28## wherein m and Y are as previously defined, such that when R₂ is H or OR₁₁, R₁ is H or OR₁₁ with R₁₁ equal to alkanoyl or ##STR29## and when R₂ is ═O, R₁ represents H or OR₁₁ with R₁₁ equal to H, alkanoyl or ##STR30## wherein m and Y are as previously defined, and when a is a 6,7 bond, R₁ can be H or OR₁₁ where R₁₁ is alkanoyl, and R₂ may be H or OR₁₁ where R₁₁ is alkanoyl; b is an optional bond, such that when b is present, Q and R₃ are H; X is O or H/OR" {wherein R" is H, alkanoyl having from 1 to 6 carbon atoms or trifluoroacetyl}; and Q is hydrogen, chlorine or bromine.
 2. The method defined in claim 1 whereinR₁ and R₂ may be the same or different and are hydrogen or OR₁₁ wherein R₁₁ is defined in claim 1 and Y is hydrogen; R₃ is --CH═CHR₃₀ wherein R₃₀ is hydrogen, alkyl having from 1 to 6 carbon atoms, phenyl or benzyl; --C.tbd.CR₃₀ ; --CHOH--C.tbd.C--R₃₀ ; --CH═C═CHR₃₀ ; --CH═N--OR₃₀ ; ##STR31## --CH═N--NHR₃₁ wherein R₃₁ is hydrogen, alkyl having from 1 to 6 carbon atoms, phenyl, benzyl, SO₂ R₃₂ and CO₂ R₃₂ wherein R₃₂ is alkyl having from 1 to 6 carbon atoms; R₄ is H or OH; a is either not present or is located in the 5,6 position in which instance R₁ is H and R₂ is OR₁₁ wherein R₁₁ is defined hereinabove; Y is hydrogen; X is O or H/OH; and Q is hydrogen or chlorine.
 3. The method defined in claim 1 wherein R₁ and R₂ may be the same or different and are hydrogen or OR₁₁ wherein R₁₁ is defined in claim 1 and Y is hydrogen;R₃ is hydrogen, alkyl having from 1 to 6 carbon atoms, --CH═CHR₃₀₁ or --C.tbd.CR₃₀₁ [wherein R₃₀₁ is hydrogen, alkyl having from 1 to 6 carbon atoms, phenyl, benzyl or CO₂ R_(c) wherein R_(c) is defined in claim 1 ]; R₄ is H or OH; R5 is OH; a is either not present or is located in the 5,6 position in which instance R₁ is H and R₂ is OR₁₁ wherein R₁₁ is defined hereinabove; Y is hydrogen; X is O or H/OH; and Q is hydrogen or chlorine.
 4. The method defined in claim 3 wherein R₄ is H.
 5. The method defined in claim 1 which utilizes 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.
 6. The method defined in claim 1 which utilizes 8,13-epoxy-1α,6β,7β-trihydroxylabd-14-en-one 7-acetate.
 7. The method defined in claim 1 which utilizes 8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one
 8. The method defined in claim 1 which utilizes 6β-acetoxy-8,13-epoxy-1α,7β,9α-trihydroxylabd-14-en-11-one.
 9. The method defined in claim 1 which utilizes 8,13-epoxy-1α,7β,9α-trihydroxy-labda-5(6),14-dien-11-one 7-acetate. 